Viral hemorrhagic fevers (VHFs) refer to severe multisystem syndrome, caused by viruses of four distinct families: arenaviruses, filoviruses, bunyaviruses, and flaviviruses. These symptoms are often accompanied by hemorrhage (bleeding). While some types of hemorrhagic fever viruses can cause relatively mild illnesses, many of these viruses cause severe, life-threatening disease. Currently, there is limited treatment or established cure for VHF infection. Ribavirin, an antiviral drug, has been effective in treating some individuals with Lassa fever or hemorrhagic fever with renal syndrome (HFRS). Treatment with convalescent-phase plasma has been used with success in some patients with Argentine hemorrhagic fever. There is a dengue vaccine, Dengvaxia®, has been approved for use in several countries, but its coverage is not complete: it is more effective for individuals 9-45 years of age, and has higher against serotypes 3 and 4 (71.6% and 76.9%, respectively) than for serotypes 1 and 2 (54.7% and 43.0%) based on the phase clinical trials.
The Ebola Outbreak in West Africa of 2014 is the largest one in history, As of Mar. 24, 2016: Laboratory-Confirmed Cases: 15,253, Total Deaths: 11,320 (74%). There are no effective medical treatments for managing Filovirus infection (Jinhong 2014). The pipeline for candidate Filovirus therapeutics is limited, but recent promising work with novel nucleotide prodrug GS-5734 (Warren et al 2016), nucleoside BCX-4430 (Biocryst Pharmaceuticals), entry inhibitors (Cote et al., 2011), post entry, s-adenosine homocystein hydrolase (SAHS) inhibitors (Huggins, Zhang, and Bray, 1999), antisense oligo (Warren et al., 2010b), immuno-adhesion (Radoshitzky et al., 2011), and chimeric monoclonal ZMapp approaches have been reported. It is unclear which, if any, of these approaches will become clinically developed; all are in very early or clinical stages. The imino sugars with known target (host ER □-glucosidases) and would be complementary to these approaches, and have the advantage of being broadly active.
Our approach to developing antiviral compounds is to design a molecule targeting host factors that are essential for the virus life cycle, thereby providing antiviral effect. In theory, by targeting host pathways used in common by all the hemorrhagic fever viruses, it should be possible to discover broad spectrum antiviral agents. If the viruses are more dependent upon the host pathway than is the host, selectivity and a useful therapeutic is possible. Viral hemorrhagic fevers (VHF) viruses each contain different RNA genomes, but they are all enveloped with glycosylated viral proteins and share a similar morphogenesis strategy of budding, which would make them sensitive to glucosidase inhibitors. This is presumably because the folding of N-linked glycoproteins in these viruses depends upon calnexin, a chaperon that folds proteins that have been trimmed by the Endoplasmic reticulum (ER) glucosidase. Most cell functions can compensate for a reduction in glucosidase enzyme function; however, the calnexin dependent viral envelope proteins cannot apparently use alternative processing pathways. Thus, glucosidase inhibitors would be selective antiviral agents against multiple enveloped viruses.
Imino sugars, such as deoxynojirimycin (DNJ) and its derivatives have been found glucosidase inhibitors. Despite great potential as broad-spectrum antivirals, clinical development of imino sugars has been limited by their low efficacy. The glucosidase inhibitors, N-butyl-DNJ (NBDNJ) currently approved by the US and European FDAs for use in the management of Gaucher's disease and Celgosivir (in Phase II human trials for Hepatitis C virus infection), both require near millimolar concentrations to achieve EC50 values in tissue culture against their target viruses. NBDNJ has been dropped for antiviral development, due to the failure to achieve therapeutic concentration in vivo. Several more potent DNJ derivatives have been prepared with submicro molar EC50 (Chang et al, 2014), but the urgent and unmet need to identify agents with broad virus coverage supports the need for continuing efforts to seek novel and more effective glucosidase inhibitors useful as antiviral agents.
Success of imino sugars as human used antiviral agents, which has in the past required constitutive high serum concentrations of drug, has been, to some extent, limited by the GI distress (diarrhea) (Butters, 2007; Durantel, 2009) caused by inhibition of intestinal glucosidases (Reuser and Wisselaar, 1994). Unlike imino sugar's antiviral target, intracellular ER □-glucosidases, these intestinal glucosidases are in the brush border of the small intestines with their active site facing the lumen. Therefore, side effects occur following oral administration (Reuser and Wisselaar, 1994), and are unrelated to antiviral efficacy (Jacob and Bryant, 1993).
Also limiting the utility of imino sugars as viable therapeutic agents is their sometimes poor pharmacokinetic properties, as shown by their high efflux ratios (Jinhong, 2013). These poor properties can limit the intestinal absorption of an agent and limit uptake into the target tissue or cell. To improve on their properties prodrugs of imino sugars have been employed. It has been demonstrated that preparation of imino sugar pan-esters improves the systemic absorption of an imino sugar (Cook, C. S.; et al. Pharmaceutical Research, 1995, 12, 1158-1164) and furthermore, the ester moiety of these “prosugars” is masked with neutral lipophilic groups to obtain a suitable partition coefficient to optimize uptake and transport into the cell dramatically enhancing the intracellular concentration of the imno sugar analog relative to administering the parent imno sugars alone (P. S. Sunkara, D. L. Taylor, M. S. Kang, T. L. Bowlin, P. S. Liu, A. S. Tyms and A. Sjoerdsma, Lancet, 1989, I, 1206).
The present invention addresses the need for new antiviral drugs that are both disease-modifying and effective in treating patients that are infected with viral hemorrhagic fever (VHFs) viruses. The present invention also addresses the long felt need for new treatments for and means of preventing diseases that involve viral infection and other diseases that involve glucosidase activity.